This invention relates to calcium phosphate cements which set after the mixing of a powdered calcium and phosphate source in an aqueous solution to form hydroxyapatite (HA). More particularly, it relates to the addition of citric acid and sodium bicarbonate to produce carbon dioxide during the setting of a calcium phosphate cement, thereby introducing macroporosity into the structure.
It is sometimes desired that bone cements and bone filler materials which harden or set have an interconnected porosity (macroporosity) throughout their structure after hardening. This interconnected porosity, if of sufficient pore size, allows for vascularization and tissue ingrowth to occur into the structure. Pores greater than 70 microns in diameter have been found to allow tissue ingrowth. This tissue ingrowth can be encouraged by coating or filling the pores with osteoinductive or osteoconductive factors such as bone morphogenic proteins (BMPs). Such factors are well known to those skilled in the art. Other therapeutic agents such as antibiotics or chemo-therapeutic agents may be introduced into the porosity by adding them to the liquid or powder.
In the past, porosity has been generated by including fillers which are soluble in physiological fluids or which are resorbed after implantation. These systems have the disadvantage that the porosity only occurs after implantation and thus the pores cannot be filled with growth factors or other therapeutic agents prior to implantation. In addition, to form the required interconnected porosity, up to 50 volume percent of resorbable filler must be added to the calcium and phosphate source precursor powdered material. This sometimes adversely affects material properties and reduces the amount of hydroxyapatite formed in the reaction of the calcium and phosphate precursors.
Also, foaming agents, such as citrimide BP which reduce the surface tension of the water have been used. However, this produces unwanted ammonium compounds when used in vivo.
U.S. Pat. No. 5,820,632 to Constantz et al. relates to a calcium phosphate cement wherein when a porous structure is desired, various additives may be included which may be leached out so as to provide for porosity in the cement. This porosity is in addition to any porosities achieved with a release of gas formed during the reaction to produce the product. Constantz et al. teaches including aggregates of soluble materials generally above 25 volume percent to develop sufficient interconnected porosity to foster bony ingrowth with the volume of aggregate normally being less than 50 volume percent. Specifically, Constantz et al. suggests the addition of calcium chloride and sodium or potassium hydroxide which are water soluble and will be leached out to provide the porosity.
U.S. Pat. No. 5,525,148 to Chow et al. teaches the use of pore forming agents that are preferably, substantially insoluble in the cement itself and can be removed by either resorbtion into body tissue, dissolution into physiological solutions, dissolution in solvents or heating after the cement has hardened. The pore forming agents taught by Chow et al. include sugar, sodium bicarbonate and phosphate salts.
Thus, there is a need to find a simple way of forming an interconnected porosity of sufficient pore size during cement hardening or setting and which avoids adding large amounts of filler to the cement. It has been found that the production or introduction of sufficient amounts of carbon dioxide gas during the reaction of the calcium and phosphate precursors to form HA produces the desired porosity.
It has been found that adding sodium bicarbonate and citric acid to the calcium and phosphate precursors to the formation of hydroxyapatite with a ratio of these acid and alkaline components selected such that the final result of their reaction does not change the pH of the aqueous solution, that a final cement having the desired porosity, sufficient hydroxyapatite and sufficient physical properties are produced.
It is an object of this invention to provide a method of preparing calcium phosphate cement compositions, which self-hardens substantially to hydroxyapatite at ambient temperatures when in contact with an aqueous medium, comprising, combining one or more sparingly soluble calcium phosphates along with an acid and base to produce a set material having an interconnected porosity.
It is another object of the invention to provide an acid and base which react to form carbon dioxide during the setting process of the calcium phosphate cement compositions and which does not alter the final pH of the mixture of the one or more sparingly soluble calcium phosphate powders when combined with the aqueous medium normally added thereto.
These and other objects of the invention are provided by a method for making a porous cement which sets to hydroxyapatite at ambient temperatures comprising mixing a powder comprising a calcium source, a phosphate source and a base with a liquid comprising an aqueous solution containing an acid wherein the calcium source and the phosphate source mix with the liquid component to form hydroxyapatite and the acid and base react to form carbon dioxide producing an interconnected porosity in the material. In the preferred embodiment, the base is a carbonate selected from the group consisting of sodium carbonate, sodium bicarbonate, calcium carbonate and calcium bicarbonate or a combination thereof. The preferred acid is selected from the group consisting of citric acid, malic acid, fumaric acid, lactic acid, succinic acid and orthophosphoric acid or a combination thereof.
The preferred calcium and phosphate sources may be selected from the group consisting of tetra-calcium phosphate, dicalcium phosphate, tricalcium phosphate and monocalcium phosphate. The chosen calcium and phosphate sources must self-set when coming into contact with an aqueous solution. This requires a combination or more calcium and/or phosphate sources. Thus, one source may be calcium alone or phosphate alone or one source may be a compound having both calcium and phosphate. The preferred ratio of acid to carbonate to produce a neutral pH has been found to be about 0.7 grams of acid to about 1.0 grams of carbonate. The preferred ratio of the acid and carbonate to the combined powdered and liquid components forming the calcium phosphate cement is about 10 to 20% by weight.
These and other objects and advantages of the present invention will become apparent from the following description of the accompanying drawings, which disclose several embodiments of the invention. It is to be understood that the drawings are to be used for the purposes of illustration only and not as a definition of the invention.